Fenofibrate Ameliorates Retinal Pigment Epithelium Injury Induced by Excessive Fat Through Upregulation of PI3K/AKT Signaling

Xue Wang; Xiaomei Liu; Radouil Tzekov; Chaofeng Yu; Jiasong Yang; Yuliang Feng; Yajun Wu; Yali Xu; Shiying Li; Wensheng Li

doi:10.2147/DDDT.S420178

Fenofibrate Ameliorates Retinal Pigment Epithelium Injury Induced by Excessive Fat Through Upregulation of PI3K/AKT Signaling

Drug Des Devel Ther. 2023 Nov 21:17:3439-3452. doi: 10.2147/DDDT.S420178. eCollection 2023.

Authors

Xue Wang^{1

2

3}, Xiaomei Liu², Radouil Tzekov⁴, Chaofeng Yu¹, Jiasong Yang^{1

5}, Yuliang Feng¹, Yajun Wu¹, Yali Xu¹, Shiying Li⁶, Wensheng Li^{1

5

7}

Affiliations

¹ Aier School of Ophthalmology, Central South University, Changsha, People's Republic of China.
² Suzhou Institute of Biomedical Engineering and Technology, University of Science and Technology of China, Suzhou, People's Republic of China.
³ Department of Ophthalmology, Second Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China.
⁴ Department of Ophthalmology, University of South Florida, Tampa, FL, USA.
⁵ Shanghai Aier Eye Hospital, Shanghai, People's Republic of China.
⁶ Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, People's Republic of China.
⁷ Shanghai Aier Eye Insititute, Shanghai, People's Republic of China.

Abstract

Purpose: This study aimed to determine the effect and its mechanism of fenofibrate on retinal pigment epithelium (RPE) injury induced by excessive fat in vitro and in vivo.

Methods: ARPE-19 cells were co-incubated with palmitic acid (PA) and fenofibric acid (the active form of fenofibrate after metabolism in vivo) and mice fed with high-fat diet (HFD) were supplemented with fenofibrate. The following methods were used: Western blot and immunofluorescent staining to determine expressions of reactive oxygen species (ROS)-associated factors and proinflammatory cytokines; electroretinogram (ERG) c-wave to evaluate RPE function; TUNEL staining to detect the apoptotic cell in RPE tissue. Additionally, ARPE19 cells were treated with PI3K/AKT inhibitor or agonist to investigate the mechanism of fenofibric acid inhibiting PA-induced RPE damage.

Results: We found that the application of PA inhibited RPE cell viability in a dose-dependent manner, and increased the levels of NAPDH oxidase 4 (NOX4), 3-nitrotyrosin (3-NT), intracellular adhesion molecule-1(ICAM1), tumor necrosis factor alpha (TNFα) and vascular endothelial growth factor (VEGF) at 400μM. The application of fenofibric acid resulted in the inhibition of NOX4, 3-NT, TNFα, ICAM1 and VEGF expression in ARPE-19 cells treated with PA. Moreover, wortmannin, as a selective inhibitor of PI3K/AKT pathway, abolished the effects of fenofibrate on the oxidative stress and inflammation in ARPE-19 cells. In addition, 740Y-P, a selective agonist of PI3K/AKT pathway, enhanced the protective action of fenofibrate. Meanwhile, in vivo dosing of fenofibrate ameliorated the downregulated amplitudes of ERG c-wave in HFD-fed mice and suppressed the HFD-induced oxidative injury and inflammatory response in RPE tissues.

Conclusion: Our results suggested that fenofibrate ameliorated RPE cell damage induced by excessive fat in vitro and in vivo, in part, through activation of the PI3K/AKT signaling pathway.

Keywords: RPE; fenofibrate; high-fat diet; inflammation; oxidative stress; palmitic acid.

MeSH terms

Animals
Fenofibrate* / pharmacology
Mice
Oxidative Stress
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Retinal Pigment Epithelium / metabolism
Signal Transduction
Tumor Necrosis Factor-alpha / metabolism
Up-Regulation
Vascular Endothelial Growth Factor A / metabolism

Substances

fenofibric acid
Fenofibrate
Proto-Oncogene Proteins c-akt
Phosphatidylinositol 3-Kinases
Vascular Endothelial Growth Factor A
Tumor Necrosis Factor-alpha

Grants and funding

K02 AR002201/AR/NIAMS NIH HHS/United States